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Aims: Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects., Methods: In this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy., Results: After six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (- 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (- 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05)., Conclusions: In conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

Aims: Inflammation is a key regulatory process that links hypercholesterolemia and immune mechanisms promoting atherosclerosis. Inflammatory biomarkers may be helpful to better define the atherosclerotic burden in patients with high cholesterol levels such as familial hypercholesterolemia (FH). Our aim was to evaluate the concentration of S100A12 protein in FH patients and its association with pulse wave velocity (PWV)., Methods: We measured glucose and lipid profile, S100A12, sRAGE, esRAGE and PWV in 39 patients with a genetically confirmed diagnosis of FH and 39 hypercholesterolemic subjects without a clinical diagnosis of FH (Dutch score ≤ 3). All subjects were on statin treatment at the time of the enrollment., Results: No difference of glucose and lipid profile was found in the two groups. FH patients had higher S100A12 plasma levels than non-FH subjects (12.87 ± 4.82 vs. 8.57 ± 4.87 ng/mL, p < 0.01). No difference of hs-CRP, sRAGE and esRAGE was found between the two groups. Also, PWV was higher in FH patients than non-FH subjects (8.63 ± 0.92 vs. 6.68 ± 0.73 m/s, p < 0.05). Finally, S100A12 was independently correlated with age (p < 0.01), genetic mutation (p < 0.01) and PWV (p < 0.001)., Conclusions: FH patients exhibited higher S100A12 levels than non-FH subjects. A novel vascular inflammation pathway, other than hs-CRP, might be useful to better characterize cardiovascular risk profile.

Aims: The association of overweight status and cardiovascular disease is not clear. In this study we aimed to investigate coronary atherosclerotic disease, evaluated as coronary artery calcium score (CACs), in overweight patients with or without abdominal obesity as defined by waist-to-hip ratio (WHR)., Methods: We enrolled 276 patients aged between 40 and 70 years, with a body mass index of 25-29.9 kg/m 2 and at least one cardiovascular risk factor. Exclusion criteria were history of diabetes, cardiovascular or renal disease. Patients were stratified in high WHR (H-WHR) or low WHR (L-WHR) group according to WHR (≥ 0.85 for women and ≥ 0.90 for men) and underwent multi-detector computed tomography for CACs. Mean carotid intima-media thickness (IMT) and plaque presence were equally assessed., Results: CACs was higher in the H-WHR group compared to L-WHR (9.05 [0.0-83.48] vs 0.0 [0.0-64.7] AU, p < 0.01); the prevalence of CACs > 0 in the H-WHR group was significantly higher than subjects with L-WHR (59.6% vs 38.5%, p < 0.001). Moreover, H-WHR group had higher mean IMT (0.64 [0.56-0.72] vs 0.59 [0.55-0.67] mm, p < 0.05) and higher carotid plaque prevalence (63.7% vs 50.8%, p < 0.05) compared to subjects with L-WHR. Logistic regression showed that H-WHR was associated with presence of CACs and carotid plaque (p < 0.01). In a multiple linear regression, WHR was positively associated with CACs and IMT (p < 0.01)., Conclusions: H-WHR is a marker of coronary and peripheral atherosclerotic burden in overweight patients.

Dyslipidemias represent a variety of quantitative and/or qualitative lipoprotein abnormalities. According to etiology, we distinguish primary dyslipidemias with strictly genetic background and secondary ones with their origin in other disease or pathological states. Diabetic dyslipidemia is a type of secondary dyslipidemia and plays an important role in determining the cardiovascular risk of subjects with type 2 diabetes. In these patients, insulin resistance is responsible for overproduction and secretion of atherogenic very low density lipoprotein. In addition, insulin resistance promotes the production of small dense low-density lipoprotein (LDL) and reduces high-density lipoprotein (HDL) production. Cardiovascular disease remains a leading cause of morbidity and mortality in diabetic patients. Previous results support the role for small, dense LDL particles in the etiology of atherosclerosis and their association with coronary artery disease. Moreover, lowering LDL cholesterol reduces the risk of cardiovascular death. Therefore, the European guidelines for the management of dyslipidemias recommend an LDL cholesterol goal < 100 mg/dL in diabetic subjects without cardiovascular events. Moreover, if triglycerides (TG) are elevated (> 400 mg/dL), they recommend a non-HDL cholesterol goal < 130 mg/dL in diabetic individuals without cardiovascular events. Statins are the first line of LDL-lowering therapy in diabetic patients and combined therapy with ezetimibe and statins could be useful in very high cardiovascular risk diabetic subjects. Furthermore, the effect of a fibrate as an add-on treatment to a statin could improve the lipid profile in diabetic individuals with high TG and low HDL cholesterol. Regarding new therapies, recent data from phase III trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably decrease LDL cholesterol. Thus, they may be useful in diabetic patients with concomitant diseases such as familial dyslipidemia, recurrent cardiovascular events, and elevated LDL cholesterol after second drug administration in addition to maximal statin dose or statin intolerance.

New recommendations for the use of glycated haemoglobin A1c (HbA1c) to diagnose prediabetes and type 2 diabetes have changed the constitution of the two populations. We aimed to investigate the pathophysiological characteristics of individuals with HbA1c-defined prediabetes and type 2 diabetes, respectively. Ten subjects with HbA1c-defined prediabetes, i.e. HbA1c from 5.7 to 6.4 % (39-46 mmol/mol), eight newly diagnosed patients with HbA1c-defined type 2 diabetes [HbA1c ≥6.5 % (≥48 mmol/mol)], and ten controls with HbA1c lower than 5.7 % (<39 mmol/mol), were studied. Blood was sampled over 4 h on two separate days after a 75 g-oral glucose tolerance test and an isoglycaemic intravenous glucose infusion, respectively. Blood was analysed for glucose, insulin, C-peptide, glucagon, and incretin hormones. Insulinogenic index, disposition index, glucagon suppression, and incretin effect were evaluated. Subjects with HbA1c-defined prediabetes showed significantly lower insulinogenic index (P = 0.02), disposition index (P = 0.001), and glucagon suppression compared with controls; and similar (P = NS) insulinogenic index and glucagon suppression and higher disposition index (P = 0.02) compared to HbA1c-diagnosed type 2 diabetic patients. The patients with type 2 diabetes showed lower insulinogenic index (P = 0.0003), disposition index (P < 0.0001), and glucagon suppression compared with the controls. The incretin effect was significantly (P < 0.05) reduced in patients with HbA1c-defined type 2 diabetes compared to subjects with HbA1c-defined prediabetes and controls. Plasma levels of incretin hormones were similar across the three groups. HbA1c associated negatively with insulinogenic index, disposition index, and incretin effect. Our findings show clear alpha- and beta-cell dysfunction in HbA1c-defined type 2 diabetes compatible with the previously described pathophysiology of plasma glucose-defined type 2 diabetes. Furthermore, in HbA1c-defined prediabetes, we show defective insulin response in combination with inappropriate suppression of glucagon, which may constitute new targets for pharmacological interventions.